After more than a century of control efforts, malaria remains one of the most devastating infectious diseases. The most important malaria vector is Anopheles gambiae s.s., which is unusual in that it feeds almost exclusively on humans. It is this strong anthropophily that is largely responsible for this species' remarkable efficiency as a malaria vector. Laboratory studies have shown that An. gambiae's strong preference for humans is based on its attraction to human odor. This malaria vector belongs to a complex of closely related species that also includes An. quadriannulatus, a zoophilic species that rarely feeds on humans. We will backcross these two species in a Quantitative Trait Loci mapping experiment to identify regions of the genome that are responsible for the attraction of An. gambiae to humans. Next, we will examine genetic variation of olfaction genes located inside the identified QTL in natural populations. This will identify those olfaction genes that have evolved under positive selection in An. gambiae, and which are likely involved in the adaptation to human hosts. Finally, we will identify genes inside QTL that are expressed at different levels in An. gambiae vs. An. quadriannulatus female olfactory organs. Olfaction genes which have a relatively high level of expression in the olfactory organs of these species are expected to be involved in the host selection difference. We expect that our investigation will identify genes responsible for An. gambiae's attraction to humans. Elucidating the genetic basis of host preference will not only significantly increase our understanding of the biology of the primary disease vector in the world, it will also contribute to the development of novel malaria control methods. We expect that the identification of anthropophily genes will be useful for the rational design of more efficient repellents/attractants for use in personal protection or mosquito traps. Importantly, anthropophily genes might also be promising targets for transgenic control efforts. A genetic modification that significantly reduces the attraction of An. gambiae to humans would have a major impact on malaria transmission, even if the transgene does not fully prevent blood feeding on humans. PUBLIC HEALTH RELEVANCE This project will identify the genes responsible for the preference of the most important malaria vector in the world, Anopheles gambiae, for blood feeding on humans. This is epidemiologically one of the most important aspects of the biology of this species, and identifying the genes involved is of major importance for designing new control strategies. For example, new repellents/attractants could be designed that specifically target these human preference genes, or these genes could be removed from natural populations by releasing a genetically modified mosquito.